Gout and Hyperuricemia
Hyperuricemia and the Development of Gout
Uric acid is a metabolic "waste product" with poor solubility in body fluids, yet its potential role as a primary antioxidant in body fluids suggests it should be kept at sufficient levels in the blood. Clearly, these diametric properties of uric acid define a range for normal blood uric acid levels. Commonly, the upper limit of this range is taken as 8.6 mg/dL in men and 7.1 mg/dL in women, (although some laboratories and research groups use different limits).15-17 Uric acid levels above this limit are considered as hyperuricemia.
Hyperuricemia is a primary risk factor for the development of gout, although it is likely that many hyperuricemic individuals will not develop symptoms.7 While the risk of a gout attack increases with blood uric acid, the annual occurrence of inflammatory gout is fairly low; persons with blood uric acid levels between 7 and 8.9 mg/dL have a 0.5‒3% change of developing the disease, which rises to 4.5% at levels over 9 mg/dL.18
Hyperuricemia without symptoms (asymptomatic hyperuricemia) is also a risk factor for other diseases. Although patients with asymptomatic hyperuricemia may never experience the symptoms of a gout attack, ultrasound studies have revealed that up to one-third may have urate deposits and evidence of inflammation in their joints and surrounding soft tissues.19
As local serum uric acid concentrations rise above their limit of solubility, monosodium urate can begin to precipitate out of the blood, forming needle-like crystals preferentially in cartilage and fibrous tissues. Here, the crystals may reside for years without causing problems.20 Urate crystals within tissues have two fates; they can re-dissolve in body fluids and reenter circulation, or may be "shed" from the tissue. Shed monosodium urate crystals can enter nearby joint spaces or bursa (the fluid-filled sacs that provide cushioning between tendons and bones around a joint), where they are quickly engulfed by immune cells. This activates a localized inflammatory response, leading to the characteristic arthritis of gout.21
Gout is commonly divided into distinct "phases" of recurrent attacks of acute gout interspersed with symptom free periods, with cumulative crystal deposition gradually contributing to a chronic condition (chronic tophaceous gout).
An attack of acute gout usually appears as a sudden inflammatory arthritis of a single joint in the lower extremities, most often the metatarsophalangeal joint of the big toe (the "ball" of the foot). At this joint, gout is called podagra. Other joints that are frequently affected include the mid-foot, ankle, knee, wrists and finger joints. The skin may be red and shiny above the affected area. Attacks often begin in the early morning and reach a peak within 6 to 24 hours. The pain is severe, and patients often cannot wear socks or touch bedsheets during flare-ups.22 Even without treatment, the attacks typically subside spontaneously within several days to two weeks. Acute gout attacks can also be accompanied by high fever and leukocytosis (elevated white blood cell count).20
Gout attacks can be triggered by a variety of factors, many of which reduce the solubility of urate in the blood; these include infection, trauma to the joint, rapid weight loss, dehydration, acidosis, and lower body temperature (which explains the timing of gout attacks and why they most frequently occur in the extremities).22
Following resolution of an acute attack, a patient can enter an "intercritical period," or a period without symptoms. Although the patient may be asymptomatic, monosodium urate crystals and low-grade inflammation can persist in the joint during this period.23 Once an initial acute gout attack has occurred, further attacks are likely to follow. Recurrent attacks of acute gout often lead to chronic tophaceous gout, in which monosodium urate deposits (tophi) form in the soft tissues, usually along the rim of the ear, over the elbow joint, and in the joints of the fingers and toes. Tophi reduce the growth and viability of bone cells (osteoblasts)24 and if left untreated, tophaceous gout can lead to significant joint erosion and loss of function.22
The Role of Hyperuricemia in Other Conditions
Although hyperuricemia is most often associated with gout, elevated blood levels of uric acid have also been associated with other diseases. Hyperuricemia and gout are both risk factors for kidney or bladder stones (urolithiasis). Both conditions increase the risk of forming not only uric acid stones, but also the more common calcium oxalate stones. The presence of calcium oxalate stones is 10‒30 times higher in gout patients than those without gout.25 Deposits of monosodium urate crystals in kidney tissues can result in kidney damage (nephropathy), either acutely by formation of crystals within the tubules of the kidney, or through a chronic inflammatory response to urate deposits in other tissues of the kidney.26 Prior to the development of uric acid lowering treatments, kidney disease occurred in up to 40% of gout patients; renal failure was the usual cause of death in 18‒25% of these patients.7
Hyperuricemia is a risk factor for cardiovascular diseases in high risk groups, and has been associated with small increases in the risk of coronary events,27 heart failure,28 and stroke.29 It is often seen in patients with hypertension; high blood pressure has long been thought to contribute to elevated blood uric acid, possibly due to reduced blood flow to the kidneys and lower urate excretion.30 However, recent experimental and epidemiological data suggest that the opposite may be true: a comprehensive review of 18 observational studies revealed that for each 1 mg/dL increase in blood uric acid, in risk of hypertension increased by 13%.31 This effect was more pronounced in women and young adults. Lowering of uric acid levels in hyperuricemic, hypertensive adolescents reduced their blood pressure as well.32 Ironically, the increased risk of cardiovascular diseases associated with hyperuricemia may be due to increases in oxidative stress: xanthine oxidase, the enzyme that synthesizes uric acid, also produces free radicals in the process.6
Hyperuricemia is an integral part of metabolic syndrome,20 and epidemiological studies have demonstrated that elevated uric acid levels substantially increase metabolic syndrome risk (and vice versa).33,34 Data from the Multiple Risk Factor Intervention Trial (MRFIT) showed hyperuricemia was associated with increased risk of type 2 diabetes, and that male patients with gout had a 41% increased risk for the disease.35